Medical treatment materials play an important role in surgery, reducing time for operation. An example of medical treatment materials is an adhesive for living tissue, which is used to adhere or block vessels or organ tissues to stop leakage of body fluid such as blood, lymph, or gas from sutured or coated tissue.
Among clinically successful and popular adhesives for living tissue is fibrin glue. (See, for example, “Bonding of Living Tissue” by Shojiro Matsuda, “Adhesion” (Japan), vol. 44, No. 1, pp. 19 to 27, Jan. 25, 2000, issued by Kobunshi Kankokai.). Fibrin glue is a two-pack hemostatic material that utilizes the principle of blood coagulation. It works as follows. Fibrinogen is converted into fibrin through the enzymatic action of thrombin. Then, Factor VIII which has been activated by thrombin crosslinks fibrin, thereby forming a fibrin clump. The disadvantage of fibrin glue is the possibility of virus infection through its use, because fibrinogen, Factor VIII, and thrombin constituting fibrin glue are materials derived from living organisms (among organism materials, material from organism such as human and animal) and the quality control for initial material and safety precaution such as inactivation or removal of virus during manufacture are not always complete. Moreover, fibrin glue is expensive, weak in adhesive strength, and complex to handle. Therefore, attempts have been made to find its substitute.
The above-mentioned thesis “Bonding of Living Tissue” also mentions a technique using a gelatin glue (GRF adhesive) as another adhesive for living tissue which has been clinically used with success. GRF is a mixture of gelatin and resorcinol which is to be crosslinked with formaldehyde and glutaraldehyde. It is characterized by high adhesive strength. It is used in the same way as fibrin glue, and it is also used for filling and adhering of a sac resulting from dissecting aneurysm of the aorta. However, it is said to induce a prevention of restoration tissue in the neighborhood of application part because formaldehyde is toxic in itself.
In view of the problems of the biological safety such as infection, in recent years, synthetic material-based tissue adhesives using no material derived from living organisms have been actively developed and some adhesives have been proposed. An example is an ethyl or isobutyl cyanoacrylate adhesive among 2-cyanoacrylate adhesives widely used for the instant adhesive (“Surgery of Stanford Type A Dissecting Aneurysm of Aorta” S. Kawada et al., “Surgical Practice” (Japan), Shindan to Chiryou-sha, vol. 32, No. 9, pp. 1250 to 1258, Sep. 1, 1990). This adhesive is characterized by its rapid adhesion and high adhesion strength because it rapidly polymerizes and cures for adhesion using moisture as a polymerization initiator. However, its cured product is harder than the corresponding living tissue and has no excellent ability to follow the movements of the living tissue. The toxicity problem of formaldehyde generated by the hydrolysis of the cured product in the living organism has also been raised.
One way to obviate these problems is proposed in JP 62-290465 A which describes an adhesive for surgical treatment that includes as a main component an NCO-terminated hydrophilic urethane prepolymer composed of p-phenylene diisocyanate (PPDI) and hydrophilic polyether polyol. In the urethane-based adhesive, first, the isocyanate group at both terminals react with water to generate carbon dioxide gas and to be converted to an amino group. Then, part of the produced amine group react with the isocyanate group and an amino group in living tissue protein also react with the isocyanate group to form urethane linkages, whereby the adhesive is cured to adhere to the living tissue. Since the cured product of the adhesive is flexible, the adhesive is capable of following the movements of living organism. However, the cured product is hardly biodegradable, may cause infection because it remains for a long time and thus has the problem of biodegradability and bioabsorbability.
On the other hand, synthetic tissue adhesives having high adhesion strength and excellent biodegradability and bioabsorbability have also been developed and applied to clinical treatments. An example is a photopolymerizable bioabsorbable adhesive (trade name: Advaseal™), which is mentioned in “Experience in Using Photopolymerizable Absorbable Hydrogel (Advaseal™)—Clinical Application”, M. Takagi et al., “Thoracic Surgery” (Japan), Nankodo, vol. 53, No. 11, pp. 951 to 953, Oct. 1, 2000. In this adhesive, acryl ester terminal group is bound to a copolymer of polyethylene glycol (primer) and polylactic acid or a copolymer of polyethylene glycol (primer) and trimethylene carbonate (sealant) and the adhesive also includes an eosin dye as a photosensitive substance. The primer is applied to a wound. Then, the sealant is applied to the wound to which the primer has been applied. Thereafter, the wound is irradiated with light (450 to 550 nm in wavelength) from a xenon light source for about 40 seconds. Irradiation brings about photopolymerization, which causes the preparation to be polymerized and cured into a hydrogel, whereby the preparation adheres to the living tissue. The hydrogel is gradually absorbed into the living body and eventually it disappears about nine months after the application. However, it is necessary to prepare an apparatus for light irradiation on an operating table to use the adhesive, which has a space limitation. The economic burden for the apparatus installation and maintenance is also heavy.
U.S. Pat. No. 6,323,278, JP 2000-502380 and JP 2002-541923 propose other methods in which a two-component mixture type crosslinking material composed of synthetic polymers each having different groups reacting with each other is applied to a tissue to form a crosslinked polymer matrix. More specifically, a first component having a nucleophilic group such as a primary amino group or a thiol group introduced in the molecular chain terminals of polyethylene glycol of a multi-branched structure is mixed with a second component having an electrophilic group such as a succinimidyl group introduced therein to form a crosslinked gel (hydrogel) (U.S. Pat. No. 6,323,278). The polyethylene glycol as the skeleton of each component is one which has a weight-average molecular weight of 10,000, so that the crosslinked product decomposes into small molecules that can be eliminated through kidneys. The adhesive is designed with biodegradation and bioabsorption taken into consideration. However, the two components have to be prepared separately in the form of solution, sprayed through separate ports of an applicator to be mixed together before use and applied to the wound. Therefore, they have to be prepared previously in anticipation of the timing of use during operation. It is difficult to immediately cope with the application.
In the meantime, it is known that polysaccharides are highly biocompatible materials. In particular, U.S. Pat. No. 5,676,964 and WO 00/27886 propose crosslinked products of polysaccharides such as hyaluronic acid having a carboxy group in the molecule. The crosslinked products of polysaccharides are formed by using an intramolecular carboxy group activated by carbodiimide, ethoxyacetylene, Woodward reagent, chloroacetonitrile (U.S. Pat. No. 5,676,964), and an activator used in peptide chemistry (WO 00/27886). For the method of crosslinking activated polysaccharides, are disclosed a crosslinking method by heating or UV light irradiation (U.S. Pat. No. 5,676,964) and a crosslinking method using polyamine (WO 00/27886).
The above-mentioned publications propose the use of the crosslinked products in the form of film, sponge, capsule, tablet, and DDS carrier for medicine and surgery, but do not disclose the use of the activated polysaccharides in uncrosslinked form.
In polysaccharide activation, a carboxy group in the polysaccharide is in the form of salt such as an ammonium salt prior to the reaction with an activator. Inactivated carboxyl residues after the polysaccharide activation are in the form of sodium salt or the like. Therefore, there is a high possibility that the crosslinked product contains residual ammonium or metallic salt.
There is a related art technique (WO 95/24429) which discloses a method of activating a polysaccharide having carboxylic acid in the molecule in the form of salt as mentioned above. It discloses an activated polysaccharide which is formed from a polysaccharide such as hyaluronic acid having a carboxy group in the molecule, by partial or complete esterification with an aromatic alcohol, heteroaromatic alcohol, or N-hydroxylamine alcohol. The activated polysaccharide will find use as an intermediate for peptide synthesis. However, the use of the activated polysaccharide in its uncrosslinked state is not disclosed, as in the above-mentioned patent documents.
As mentioned above, the medical treatment materials typified by tissue adhesives which are used in a living body should meet clinical requirements for not only adhesion strength but also safety, and it is important to design the materials taking into account avoidance of infection by the use of materials not derived from living organism, reduction of the toxicity of the components or a decomposed product by the use of a synthetic material, and biodegradability and bioabsorbability. Moreover, they should be available at any time when necessary without requiring preliminary steps during operation and without requiring special equipment for their use.